NZ582352A - Pyrimidine derivatives useful as raf kinase inhibitors - Google Patents

Pyrimidine derivatives useful as raf kinase inhibitors

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Publication number
NZ582352A
NZ582352A NZ582352A NZ58235208A NZ582352A NZ 582352 A NZ582352 A NZ 582352A NZ 582352 A NZ582352 A NZ 582352A NZ 58235208 A NZ58235208 A NZ 58235208A NZ 582352 A NZ582352 A NZ 582352A
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NZ
New Zealand
Prior art keywords
april
recieved iponz
compound
formula
optionally substituted
Prior art date
Application number
NZ582352A
Inventor
Weirong Chen
Jennifer Cossrow
Lioyd Franklin
Bing Guan
John Howard Jones
Gnanasambandam Kumaravel
Benjamin Lane
Adam Littke
Alexey Lugovskoy
Hairuo Peng
Noel Powell
Brian Raimundo
Hiroko Tanaka
Jeffrey Vessels
Thomas Wynn
Zhili Xin
Original Assignee
Millennium Pharm Inc
Sunesis Pharmaceuticals Inc
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Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=40029124&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=NZ582352(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Millennium Pharm Inc, Sunesis Pharmaceuticals Inc filed Critical Millennium Pharm Inc
Publication of NZ582352A publication Critical patent/NZ582352A/en

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Abstract

Disclosed is a compound of formula I e.g. 2-(1-(6-acetamidopyrimidine-4-carboxamido)ethyl)-N-( 5-chloro-4-(trifluoromethyl)pyridin-2-yl)thiazole-5-1H-carboxamide or a pharmaceutically acceptable salt thereof, wherein: disorder is selected from a proliferative disorder, a cardiac disorder, a neurodegenerative disorder, an autoimmune disorder, a condition associated with organ transplant, an inflammatory disorder, an immunologically-mediated disorder, a viral disease, or a bone disorder.

Claims (43)

WO 2009/006389 259 PCT/US2008/068762 [0382] Certain compounds of the present invention were assayed using the above cellular assays and were found to be inhibitors of Raf kinase. [0383] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example. RECIEVED IPONZ 26 APRIL 2012 260 What we claim is:
1. A compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: Cy1 is an optionally substituted phenyl or an optionally substituted 5-6 membered aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Cy2 is an optionally substituted 5-14 membered saturated, partially unsaturated, or aromatic monocyclic, bicyclic, or tricyclic ring having 0-4 heteroatoms, independently selected from nitrogen, oxygen, or sulfur; L1 is a direct bond or an optionally substituted, straight or branched Cj_6 alkylene chain; L2 is a direct bond, or is an optionally substituted, straight or branched Ci_6 alkylene chain wherein 1 or 2 methylene units of L2 are optionally and independently replaced by -0-, -S-, -N(R)-, -C(O)-, -C(0)N(R)-, -N(R)C(0)N(R)-, -N(R)C(0)-, -N(R)C(0)0--0C(0)N(R)-, -S02-, -S02N(R)-, -N(R)S02~, -OC(O)-, -C(0)0-, or a 3-6 membered cycloalkylene; each R is independently hydrogen or an optionally substituted Cj-6 aliphatic group; R1 is hydrogen or an optionally substituted Ci_6 aliphatic group; each of Rx and Ry is independently selected from -R2, -halo, -N02, -CN, -OR2, -SR2, -N(R2)2, -C(0)R2, -C02R2, -C(0)C(0)R2, -C(0)CH2C(0)R2, -S(0)R2, -S(0)2R2, -C(0)N(R2)2, -S02N(R2)2, -0C(0)R2, -N(R2)C(0)R2, -N(R2)N(R2)2, -N(R2)-C(=NR2)N(R2)2, -C(=NR2)N(R2)2, -C=NOR2, -N(R2)C(0)N(R2)2, -N(R2)S02N(R2)2, -N(R2)S02R2, or -0C(0)N(R2)2; and each R2 is independently hydrogen or an optionally substituted group selected from Ci_6 aliphatic, a C6-10 monocyclic or bicyclic aryl ring, or a 5-10 membered saturated, partially unsaturated, or aromatic monocyclic or bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or RECIEVED IPONZ 26 APRIL 2012 261 two R on the same nitrogen are taken together with the nitrogen to form an optionally substituted 5-8 membered saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
2. The compound according to claim 1, wherein each of Rx and Ry is independently selected from R2, halo, -OR2, -N(R2)2, -0C(0)R2, -N(R2)C(0)R2, -N(R2)N(R2)2, -N(R2)C(0)N(R2)2, -N(R2)S02N(R2)2, ~N(R2)S02R2, or -0C(0)N(R2)2.
3. The compound according to claim 2, wherein Rx is hydrogen, an optionally substituted Ci_6 aliphatic group, or halo.
4. The compound according to claim 2 or claim 3, wherein Ry is selected from R2, -OR2, or -N(R2)2.
5. The compound according to claim 4, wherein Ry is -NH2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2, -NH(C3H5), -NHCH2CH2CH20H, -N(CH2CH2)20, or -NHCH2CH2CH2NH(CH3)2.
6. The compound according to claim 4, wherein Ry is an optionally substituted Ci_6 aliphatic group.
7. The compound according to claim 6, wherein Ry is an optionally substituted group selected from C2_^ alkenyl or C2_6 alkynyl.
8. The compound according to claim 4, wherein Ry is an optionally substituted 5-10 membered saturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
9. The compound according to claim 8, wherein Ry is an optionally substituted group selected from: (a) a 5-6 membered saturated monocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; (b) a 5-6 membered aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or RECIEVED IPONZ 26 APRIL 2012 262 (c) an 8-10 membered saturated, partially unsaturated or aromatic bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
10. The compound according to claim 8, wherein Ry is an optionally substituted group selected from phenyl, octahydroazocinyl, thiocyclopentanyl, thiocyclohexanyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrothiopyranyl, tetrahydrothiophenyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, thioxanyl, morpholinyl, oxathiolanyl, imidazolidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiophenyl, furanyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrahydropyridinyl, benzofuranyl, thianaphthenyl, pyrrolizinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, imidazopyridinyl, purinyl, indazolyl, pyrrolopyridinyl, cinnolinyl, quinazolinyl, phthalazinyl, naphthyridinyl, or quinoxalinyl.
11. The compound according to any one of claims 1 to 10, wherein R1 is hydrogen and L1 is an optionally substituted, straight or branched C1-4 alkylene chain.
12. The compound according to any one of claims 1 to 11, wherein Cy1 is an optionally substituted 5-membered aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
13. The compound according to claim 12, wherein Cy1 is an optionally substituted pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiophenyl, furanyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, or oxadiazolyl group. • 2 • •
14. The compound according to any one of claims 1 to 13, wherein L is a direct bond or an optionally substituted, straight or branched C1-4 alkylene chain wherein 1 or 2 methylene units of L2 are replaced by -0-, -S-, -N(R)-, -C(O) , - C(0)N(R)-, -N(R)C(0)N(R)-, -N(R)C(0)-, -N(R)C(0)0-, -0C(0)N(R)-, -S02-, -S02N(R)-, -N(R)S02-, -OC(O)-, or-C(0)0-.
15. The compound according to claim 14, wherein L2 is -C(0)N(R)-, -N(R)C(0)-, -S02N(R)-, -N(R)S02-, -OC(O)-, or -C(0)0-.
16. The compound according to claim 15, wherein L2 is -C(0)N(H)- or -N(H)C(0)-. RECIEVED IPONZ 26 APRIL 2012 263
17. The compound according to any one of claims 1 to 16, wherein Cy2 is an optionally substituted group selected from: (a) a 5-membered saturated, partially unsaturated, or aromatic monocyclic ring having 1-4 heteroatoms, independently selected from nitrogen, oxygen, or sulfur; (b) phenyl or a 6-membered saturated, partially unsaturated, or aromatic monocyclic ring having 1-4 heteroatoms, independently selected from nitrogen, oxygen, or sulfur; or (c) a 5-10 membered saturated, partially unsaturated, or aromatic bicyclic ring having 1-4 heteroatoms, independently selected from nitrogen, oxygen, or sulfur.
18. The compound according to claim 17, wherein Cy2 is an optionally substituted group selected from: (a) a 5-membered heteroaryl ring having 1-4 heteroatoms, independently selected from nitrogen, oxygen, or sulfur; (b) phenyl or a 6-membered heteroaryl ring having 1-3 nitrogen atoms; or (c) a 5,6-fused bicyclic heteroaryl ring having 1-4 heteroatoms selected from oxygen,
19. The compound according to claim 18, wherein Cy2 is an optionally substituted group selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiophenyl, furanyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, pyrrolizinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, imidazopyridinyl, indazolyl, purinyl, cinnolinyl, quinazolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, thianaphthenyl, or benzofuranyl.
20. The compound according to claim 1, wherein said compound is of formula II: sulfur or nitrogen. II or a pharmaceutically acceptable salt thereof. RECIEVED IPONZ 26 APRIL 2012 264
21. The compound according to claim 20, wherein said compound of formula II is of formula II-a or Il-b: II-a Il-b or a pharmaceutically acceptable salt thereof.
22. The compound according to claim 21, wherein Cy1 is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
23. The compound according to claim 1, wherein said compound is selected from the following: RECIEVED IPONZ 26 APRIL 2012 265 RECIEVED IPONZ 26 APRIL 2012 266 RECIEVED IPONZ 26 APRIL 2012 267 RECIEVED IPONZ 26 APRIL 2012 268 RECIEVED IPONZ 26 APRIL 2012 269 RECIEVED IPONZ 26 APRIL 2012 270 RECIEVED IPONZ 26 APRIL 2012 271 RECIEVED IPONZ 26 APRIL 2012 272 RECIEVED IPONZ 26 APRIL 2012 273 RECIEVED IPONZ 26 APRIL 2012 274 H RECIEVED IPONZ 26 APRIL 2012 275 RECIEVED IPONZ 26 APRIL 2012 276 RECIEVED IPONZ 26 APRIL 2012 277 RECIEVED IPONZ 26 APRIL 2012 278 RECIEVED IPONZ 26 APRIL 2012 279 RECIEVED IPONZ 26 APRIL 2012 280 Hjts RECIEVED IPONZ 26 APRIL 2012 282 RECIEVED IPONZ 26 APRIL 2012 283 H,N RECIEVED IPONZ 26 APRIL 2012 RECIEVED IPONZ 26 APRIL 2012 285 \ F G. ,N. RECIEVED IPONZ 26 APRIL 2012 286 RECIEVED IPONZ 26 APRIL 2012 287 RECIEVED IPONZ 26 APRIL 2012 288 RECIEVED IPONZ 26 APRIL 2012 289 RECIEVED IPONZ 26 APRIL 2012 290 RECIEVED IPONZ 26 APRIL 2012 292 RECIEVED IPONZ 26 APRIL 2012 293 RECIEVED IPONZ 26 APRIL 2012 294 h /cfs h r°yJ> p CFS O^N .g/ HN—\—Me "n NN JJ RECIEVED IPONZ 26 APRIL 2012 295 P Pf3 H /=(CF3 H r yi ^ vN Y^HN-Q-Me RECIEVED IPONZ 26 APRIL 2012 296 RECIEVED IPONZ 26 APRIL 2012 297 RECIEVED IPONZ 26 APRIL 2012 298 RECIEVED IPONZ 26 APRIL 2012 RECIEVED IPONZ 26 APRIL 2012 300 RECIEVED IPONZ 26 APRIL 2012 301 RECIEVED IPONZ 26 APRIL 2012 302 RECIEVED IPONZ 26 APRIL 2012 303 RECIEVED IPONZ 26 APRIL 2012 RECIEVED IPONZ 26 APRIL 2012 305 306 RECIEVED IPONZ 26 APRIL 2012 H OyN~ CIV^N RECIEVED IPONZ 26 APRIL 2012 307 RECIEVED IPONZ 26 APRIL 2012 308 RECIEVED IPONZ 26 APRIL 2012 309 RECIEVED IPONZ 26 APRIL 2012 310 CI RECIEVED IPONZ 26 APRIL 2012 311 RECIEVED IPONZ 26 APRIL 2012 312 RECIEVED IPONZ 26 APRIL 2012 313 RECIEVED IPONZ 26 APRIL 2012 314 RECIEVED IPONZ 26 APRIL 2012 315 RECIEVED IPONZ 26 APRIL 2012 316 RECIEVED IPONZ 26 APRIL 2012 317 \—"j, NX J h2n n -NY^HN-^J-r i RECIEVED IPONZ 26 APRIL 2012 318 RECIEVED IPONZ 26 APRIL 2012 319 RECIEVED IPONZ 26 APRIL 2012 320 F F F F RECIEVED IPONZ 26 APRIL 2012 h ck. ,n. a. H,! D-< 321 a h,n. ci o f n^/n H 11 // n nh or a pharmaceutically acceptable salt thereof.
24. The compound: CF, H2N CI H N , or a salt thereof
25. A compound of formula II-/v: II-/V wherein Cy1 is an optionally substituted 5-6 membered saturated, partially unsaturated, or aromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and Cy2 is an optionally substituted 5-10 membered saturated, partially unsaturated, or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms, independently selected from nitrogen, oxygen, or sulfur.
26. The compound according to claim 1, wherein the compound is: RECIEVED IPONZ 26 APRIL 2012 322 or a pharmaceutically acceptable salt thereof.
27. A pharmaceutical composition comprising a compound according to any one of claims 1 to 26, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
28. The composition of claim 27, in combination with a therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders.
29. A method of inhibiting Raf kinase activity in an isolated biological sample, which method comprises contacting said isolated biological sample with a compound according to any one of claims 1 to 26, or a pharmaceutical composition thereof.
30. Use of a compound according to any one of claims 1 to 26 in the manufacture of a medicament for treating or lessening the severity of a Raf-mediated disorder in a mammal suffering such disorder, wherein the disorder is selected from a proliferative disorder, a cardiac disorder, a neurodegenerative disorder, an autoimmune disorder, a condition associated with organ transplant, an inflammatory disorder, an immunologically-mediated disorder, a viral disease, or a bone disorder.
31. The use according to claim 30, wherein the disorder is selected from melanoma, leukemia, colon cancer, breast cancer, gastric cancer, ovarian cancer, lung cancer, brain cancer, laryngeal cancer, cervical cancer, renal cancer, cancer of the lymphatic system, cancer of the genitourinary tract (including bladder cancer and prostate cancer), stomach cancer, bone cancer, lymphoma, glioma, papillary thyroid cancer, neuroblastoma, and pancreatic cancer.
32. The use according to claim 31, wherein the medicament is formulated to further comprise an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an RECIEVED IPONZ 26 APRIL 2012 323 agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders, wherein: said additional therapeutic agent is appropriate for the disease; and said medicament is formulated for administration of said additional therapeutic agent together with said compound as a single dosage form or separately from said compound as part of a multiple dosage form.
33. A method for preparing a compound of formula II-a': or a pharmaceutically acceptable salt thereof, wherein: Cy1 is an optionally substituted 5-6 membered saturated, partially unsaturated, or aromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Cy2 is an optionally substituted 5-10 membered saturated, partially unsaturated, or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms, independently selected from nitrogen, oxygen, or sulfur; each of Rx and Ry is independently selected from -R2, -halo, -NO2, -CN, -OR2, -SR2, -N(R2)2, -C(0)R2, -CO2R2, -C(0)C(0)R2, -C(0)CH2C(0)R2, -S(0)R2, -S(0)2R2, -C(0)N(R2)2, -S02N(R2)2, -0C(0)R2, -N(R2)C(0)R2, -N(R2)N(R2)2, -N(R2)-C(=NR2)N(R2)2, -C(=NR2)N(R2)2, -C=NOR2, -N(R2)C(0)N(R2)2, -N(R2)S02N(R2)2, -N(R2)S02R2, or -0C(0)N(R2)2; each R2 is independently hydrogen or an optionally substituted group selected from C\s aliphatic, a C6-10 monocyclic or bicyclic aryl ring, or a 5-10 membered saturated, partially unsaturated, or aromatic monocyclic or bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two R2 on the same nitrogen are taken together with the nitrogen to form an optionally substituted 5-8 membered saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, II-a' RECIEVED IPONZ 26 APRIL 2012 324 comprising the step of coupling a compound of formula II-v«7: n oh ll-viii with a compound of formula II-vw: II-VM to form the compound of formula II-a'.
34. The method according to claim 33, wherein the compound of formula ll-vii is prepared from a compound of formula II-vi-b: © ©A II -vi-b wherein A" is a suitable chiral anion, comprising the step of treating the compound of formula l\-vi-b with a suitable base to form a compound of formula ll-vii.
35. The method according to claim 34, wherein the compound of formula II-vi-b is prepared from a compound of formula II-v: comprising the steps of: (a) treating the compound of formula II-v with a chiral agent to form a compound of formula II-v/-a: II-v, RECIEVED IPONZ 26 APRIL 2012 325 © ©A ll-vi-a and (b) separating the resulting diastereomers by suitable physical means to obtain a compound of formula II-vi-Z>.
36. The method according to claim 35, wherein the compound of formula II-v: II-v is prepared from a compound of formula II-iv: II-IV comprising the step of converting the oxime moiety of formula II-iv to the amine group of formula II-v.
37. The method according to claim 36, wherein the compound of formula II-iv is prepared from a compound of formula II-iii: II-iii comprising the step of treating the compound of formula II-iii with hydroxylamine to form the compound of formula II-iv.
38. The method according to claim 37, wherein the compound of formula II-iii is prepared by coupling a compound of formula Il-i: RECIEVED IPONZ 26 APRIL 2012 326 O O II-/ with a compound of formula II-//: II-H.
39. A compound of formula I as defined in claim 1, and substantially as hereinbefore described with reference to one or more of the accompanying examples.
40. A compound of formula II-iv as defined in claim 25, and substantially as hereinbefore described with reference to one or more of the accompanying examples.
41. A pharmaceutical composition comprising a compound according to claim 39 or claim 40, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
42. A method of inhibiting Raf kinase activity in an isolated biological sample, which method comprises contacting said isolated biological sample with a compound according to claim 39 or claim 40, or a pharmaceutical composition thereof.
43. Use of a compound according to claim 39 or claim 40 in the manufacture of a medicament for treating or lessening the severity of a Raf-mediated disorder in a mammal suffering such disorder, wherein the disorder is selected from a proliferative disorder, a cardiac disorder, a neurodegenerative disorder, an autoimmune disorder, a condition associated with organ transplant, an inflammatory disorder, an immunologically-mediated disorder, a viral disease, or a bone disorder. Millennium Pharmaceuticals, Inc. Sunesis Pharmaceuticals, Inc. By the patent attorneys for the applicants CULLENS
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